Single nucleotide substitutions and small unique base insertions or deletions are the most frequent form of DNA polymorphism and disease- causing mutation in the human genome. Therefore, it is important to develop highly accurate and efficient methods to identify and type these changes in populations. In fact, our ability to evaluate the relevance of specific variations with regard to phenotype will likely hinge on these issues. The goal of this project is to increase the speed and accuracy of automated approaches for identifying and typing DNA variations by improving base-calling software for automated sequencers. We will focus the development of this software around a project designed to scan the major human T cell receptor loci for sequence variation. Since T cells play a central role in the generating and regulating an immune response, a greater understanding of the natural variation in these genes may provide new insights into differences in immune function among human populations particularly with regard to resistance to infection or cancer, or in terms of susceptibilities to disorders such as autoimmune diseases or immune mediated hypersensitivities. Lastly, this project focuses on the development of automated DNA sequencing as a highly sensitive approach that can be applied not only identifying DNA polymorphisms and mutations in T cell receptor genes but also broadly to any other gene for genetic and disequilibrium mapping, DNA diagnostics (genetic and infectious diseases), tissue typing, and forensic testing.